Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription

Shiladitya Sengupta, Haibo Wang, Chunying Yang, Bartosz Szczesny, Muralidhar L. Hegde, Sankar Mitra

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Among several reversible epigenetic changes occurring during transcriptional activation, only demethylation of histones and cytosine-phosphate-guanines (CpGs) in gene promoters and other regulatory regions by specific demethylase(s) generates reactive oxygen species (ROS), which oxidize DNA and other cellular components. Here, we show induction of oxidized bases and single-strand breaks (SSBs), but not direct double-strand breaks (DSBs), in the genome during gene activation by ligands of the nuclear receptor superfamily. We observed that these damages were preferentially repaired in promoters via the base excision repair (BER)/ single-strand break repair (SSBR) pathway. Interestingly, BER/SSBR inhibition suppressed gene activation. Constitutive association of demethylases with BER/SSBR proteins in multiprotein complexes underscores the coordination of histone/DNA demethylation and genome repair during gene activation. However, ligand-independent transcriptional activation occurring during heat shock (HS) induction is associated with the generation of DSBs, the repair of which is likewise essential for the activation of HS-responsive genes. These observations suggest that the repair of distinct damages induced during diverse transcriptional activation is a universal prerequisite for transcription initiation. Because of limited investigation of demethylation-induced genome damage during transcription, this study suggests that the extent of oxidative genome damage resulting from various cellular processes is substantially underestimated.

Original languageEnglish (US)
Pages (from-to)22183-22192
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number36
DOIs
StatePublished - Sep 8 2020

Keywords

  • Base excision/single-strand break repair
  • DNA demethylation
  • Histone demethylation
  • Oxidative genome damage
  • Transcriptional activation

ASJC Scopus subject areas

  • General

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